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Home , Ernest Rutherford, George de Hevesy, Hilde Levi

Georg Charles de Hevesy: The Father of Nuclear

William G. Myers

College of Medicine, The Ohio State University, Columbus, Ohio

experiments with such minuscule concentrations of lead as to J Nucl Med Techno/1996; 24:291-294 avoid the toxic properties of it. He proved also that the lead taken up by the plants was present in them in ionizable form (1,2). It is especially timely and fitting at the end of the first The following year Hevesy published with Christiansen and quarter of a century of the existence of the Society of Nuclear Lomholt (1) the results of the first experiments in animals in Medicine to realize that the commemorative presentation at which radiochemical methods were employed. They used 5.0- our annual meeting will be designated henceforth as the day 210Bi (RaE) to label and to follow the circulation of Hevesy Pioneer Lecture. In this manner we bismuth in the bodies of rabbits after intramuscular injections will be reminded each year of "the one who started it all" and of antisyphilitic medicaments containing bismuth. Similarly, thereby acknowledge our gratitude and indebtedness to him they used 22.3-yr 210Pb (RaD) as a radioindicator to follow the for the immense impact of his intuition on our lore. Much of excretion and the distribution of lead in several organs after the basic origins of nuclear medicine stemmed from the in­ injection of labeled lead hydroxide mixed with olive oil (1 ). sights and the seminal contributions of Professor Hevesy. The The measurements were made at the Institute of Theoretical consuming drive of his scientific curiosity and his indefatigable (now The Bohr Institute) at the University of Copen­ enterprise made of him the towering intellectual genius that he hagen, where Hevesy pursued many of his investigations. was. There he enjoyed the appreciative interest of his cherished Manifestations of Hevesy's manifold and vividly imaginative friend, . pioneering investigations, which spanned more than a half While Hevesy was in a dozen years previously, century, were chronicled fittingly in the 1047 pages of two Professor Ernest importuned the young to monumental volumes published in 1962 (1) and aptly titled, separate radioactive 210Pb from its admixture with the large Adventures in Radioisotope Research. Here are reprinted, in amounts of nonradioactive lead in the laboratory there by translation into English from as many as four other languages, saying to him (1) "If you are worth your salt, you separate a selection of 100 of his nearly 400 publications, together with D from all that nuisance of lead." For two years, intercalations of numerous commentaries of invaluable histor­ Hevesy tried in vain to carry out the separation by chemical ical content. methods. Failing in this, he concluded the great sensitivity of Although Hevesy's training lay principally in the field of physical methods for measuring radioactivity would make im­ physical , his interests were highly diverse and his ponderable amounts of 210Pb an excellent radioindicator tracer prodigious endeavors penetrated into many areas of science. to "represent" nonradioactive lead in qualitative and Specifically important to us in nuclear medicine was his dis­ quantitative processes. Thus, Hevesy's fertile imagination con­ covery of the indicator tracer method of analysis and the verted adversity into advantage and the concept of radioindi­ initiation of applications of it in biomedicine. cator chemistry was born! Frustration from his failure seren­ It was Hevesy who, in 1923, first used a naturally radioactive dipitously had led to triumph and to the discovery of the most , 10.6-hr 212Pb (ThB), to study the uptakes of labeled sensitive method of analysis. lead ions from dilute solutions by the roots, stem, leaves and When Hevesy went to the Vienna Radium Institute early in fruit of vicia faba (horse bean). He used an electroscope to 1913, he found Dr. Fritz Paneth had been working quite inde­ assay the relative amounts of radioactivity present in ashed pendently there on the same problem, and with the same samples of parts of the plants. Because of the extreme sensi­ fruitless results. The two young then decided to pub­ tivity of physical radioassay methods, he carried out these lish jointly their findings on the chemical inseparability of 210Pb (RaD) from nonradioactive lead. They also published together the use of 210Pb as a radioindicator tracer to analyze Reprinted from: Myers WG. Georg Charles de Hevesy: the father of nuclear medicine. J Nucl Med 1979;20:590-594. quantitatively the slight solubilities of lead sulfide and lead

VOLUME 24, NUMBER 4, DECEMBER 1996 291 chromate (1,3,4). In these papers they introduced the method 10-min 13N (6). Within several months, Fermi and his students and the technical terminology, "radioelements as indicators." used a -beryllium source in Rome in their dis­ These two publications in 1913 constituted the first in which coveries of a large number of radionuclides of many elements. radioindicator tracers played a unique role in chemical analy­ Among them was 14.3-day 32P. sis. Twenty-five years later in their book (5), A Manual of Hevesy recognized immediately the potential applicability of Radioactivity, these two pioneers clearly defined their term, this convenient radioactive form of a "vital" element to extend "indicator." ... In problems of this kind, in which the radio­ his radioindicator method to studies of diverse natural meta­ element is not the object but the agent of the investigation, we bolic processes. Within a year after 32P was discovered he say that the radio-elements serve as "indicators,' (5 ) .... An published with Chievitz (chief of surgery at the Finsen Hospital indicated element is an element containing a small amount of in ) the first radioindicator study in the life sci­ an isotopic element which serves as an indicator for the pur­ ences with a man-made radionuclide (1 ). "Radioactive Indi­ pose of detection or measurement." (5 ). cators in the Study of Phosphorus in Rats" ap­ While with Rutherford in Manchester in 1911, Hevesy per­ peared in Nature in 1935 (7). This landmark contribution was formed a delightfully imaginative and practical experiment to reprinted in The Journal of Nuclear Medicine in 1975 (8), along demonstrate that the landlady in his boarding house was recy­ with my commentary and with a picture I made of Hevesy in cling food. It seems she had been serving freshly-prepared 1950. Phosphorus-32 "can be utilized as an indicator of inactive meat only on Sunday and then disguised it in servings of hash, phosphorus in the same way that the radioactive of goulash and other forms the rest of the week. When Hevesy lead, bismuth and so on were formerly used as indicators of cautiously suggested it would be tasty to have freshly-cooked these elements." meat served more frequently than once a week, she retorted A strong neutron source was immersed in 10 liters of carbon indignantly that she served it eve1; day. Hevesy was a sparse disulfide for some weeks to generate about a microcurie of 32P eater; and so, to prove her assertion was not true, he "spiked" in the 32S( n, p )32P transmutation (I). The 32P thus obtained a scrap of leftover meat on his plate one day with a tiny amount was converted into 32P-phosphate before placing it on bits of of a radioactive material. A few days later he brought an bread to feed to rats. Geiger-Mi.iller detectors were used to electroscope to the table to demonstrate to her that the hash assay the amounts of 32P found in various organs and excreta served that day was radioactive. "This is magic,'' she exclaimed! as a function of time. Among interesting findings was that the This labeling of food, under such piquant circumstances, may average time spent by a phosphorus in the rat was about have been the first tagging experiment in the life sciences, two months. This first biomedical study with artificial radioac­ although, unfortunately, it was of course not published for­ tivity led to the conclusion there is a rapid turnover of phos­ mally. phorus atoms in bone. Thus emerged the concept of the dynamic Hevesy used radioindicator methods during the decade be­ state of the body constituents. tween 1913 and 1923 in several radiochemical determinations; Hevesy now hit his stride in applying radioindicators in and many of his publications were coauthored with Paneth. biomedicine. As radionuclides of additional "biochemical" el­ Some of his papers involved colloid chemistry or electrochem­ ements e4 Na, 42K, etc.) soon were discovered and became istry, and others were concerned with self- in metals available, chiefly by generating them with cyclotrons, he de­ (1 ). Also, partial separations of isotopes of mercury and of voted his time increasingly to applying them in studies of a chlorine were effected with Bronsted. large variety of metabolic and physiological processes. The In 1923, Hevesy and Coster found the missing element 72 results found in most of these were reprinted in 1962 (1 ), as and named it , after the Latin name for Copenhagen, noted previously. in honor of the city where the discovery was made, and of His interests remained broad, however. In 1936, only four which Hevesy was particularly fond. years after Chadwick discovered the neutron in England, Hevesy and Hofer, in 1934, first used in medicine an en­ Hevesy and used it in Copenhagen in their discov­ riched stable isotope to determine the rate of elimination of ery of neutron radioactivation analysis. This sprang from stud­ water from the human body (1 ). They drank dilute deuterated ies of the rare earth elements ( 1 ) and of several other elements water, HOD, discovered by Urey only two years previously, and (1 ). assayed the further isotopic dilution of the in their Radioactive Indicators was the title of Hevesy's 556-page urine. From their results they concluded the average time a book, published in 1948 (9). It is a landmark contribution in water molecule spent in their bodies was 13 ± 1.5 days. which he succinctly summarized in quite complete review the "Chance only favors the prepared mind,'' wrote Pasteur. basic concepts and the experimental findings in our subject to Hevesy's brilliant mind and previous pioneering experiences that time. Hevesy did not function in isolation but kept abreast with applications in biomedicine of natural radionuclides, and of developments in applications of indicator tracer methodol­ with a stable one, had prepared him fully and well to embrace ogy in biomedical laboratories throughout the world. This immediately new opportunities to exploit the discoveries of book constituted also a turning point in the history of nuclear radioindicators of "biochemical/physiological" elements simi­ medicine; for, almost all of the myriads of measurements made larly. Frederic Joliot and Irene Curie discovered artificial ra­ by the numerous investigators had depended on assays made in dioactivity early in 1934 by creating in their laboratory in Paris vitro, chiefly of beta particles, by means of Geiger-Mi.iller positron emitters of two "biological" elements, 2.5-min 30P and detectors or electroscopes.

292 JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY Hevesy himself seems to have used methods of assay in vivo My doctor of medicine thesis on "Applications of The Cy­ by means of penetrating gamma rays little, if at all. In 1948, clotron and Its Products in Biomedicine" was written early in also, a new era dawned with the discovery of the Nal(TI) 1941, only seven years after artificial radioactivity was de­ scintillation detector by Hofstadter (10). Its much greater scribed ( 6 ). I appreciated the role this epoch-making discovery efficiency of interaction with gamma rays and other advantages already had had on Hevesy's insights and increased productiv­ soon led to the "inside-out" assays and imaging that now ity by noting that 16 of the 87 references cited in the review dominate the explosive expansion of Hevesy's concepts into were authored by Hevesy and coworkers (14 ). clinical nuclear medicine. Hevesy's firsthand acquaintanceships with Niels Bohr, Marie Hevesy received the for chemistry in 1943 "for and Irene Curie, Frederic Joliot, , Fritz Paneth, his work on the use of isotopes as tracer elements in researches and many other of the "greats" in basic on chemical processes." In his Nobel lecture on "Some Appli­ nuclear science made of him an eyewitness historian of many cations of Isotopic Indicators" (/, 11 ), he stated, "The most momentous events. That he was an able reporter of these was remarkable result obtained in the study of the application of reflected in his giving of our second Nuclear Pioneer Lecture isotopic indicators is perhaps the discovery of the dynamic on June 15, 1961 in Pittsburgh at the eighth annual meeting of state of the body constituents. The molecules building up the the Society of Nuclear Medicine, " and Her Con­ plant or animal organism are incessantly renewed." temporaries: The -Curie Memorial Lecture" (15 ). Near the end of his Faraday Lecture in 1950 ( 1,12) on "The Hevesy already had been made an honorary member of the Applications of Radioactive Indicators in Biochemistry," Society of Nuclear Medicine, in 1959. Hevesy said: The Gesellschaft fiir Nuklearmedizin began to honor Hevesy a decade ago by awarding the Hevesy Prize and by the giving of the Hevesy Lecture annually. This prize first was The application of isotopic indicators opened the only way to given to Dr. H. Saul Winchell at the meeting in Zurich in 1969, determine the rate, place and sequence of formation of and he gave the lecture the first time then also. At the Gesell­ many molecular constituents of the living organism. The very schaft meeting in 1976 in Berlin, Dr. Henry Wagner gave the existence of such methods was instrumental in opening new Hevesy Lecture; and his appreciation of the scientist led him trains of thought ... in concentrating our interest on the later to coin the aphorism (16 ), "Biochemical motion-What problem of the velocity of the fundamental biological pro­ Hevesy conceived, we now perceive." How true! Dr. Rosalyn cesses .... The indicator chemist is to some extent an histo­ Yalow gave the Hevesy Lecture and received the Hevesy rian, highly interested in the past of atoms, molecules and Medal in Madrid in 1978 at the 16th annual meeting of the molecular aggregates. He has a great concern in the distinc­ Gesellschaft fiir Nuklearmedizin. In her essay on "Radioim­ tion of how far molecules present in the tissue are "old" or munoassay: Past, Present and Potential," she expressed regret "new." ... He wishes to know when the potassium atoms for not having met Hevesy, but regarded him through his book present in the tissue cells left the circulation. in 1948 (9) almost as having been her teacher. In her lecture when she received the Nobel Prize for medicine in 1977, she Another instance of Hevesy's keen sense of history was acknowledged Hevesy as a scientific progenitor of her career illustrated in his handwritten letter to on (17). January 14, 1938 when he thanked Lawrence for mailing suf­ Hilde Levi worked closely with Hevesy as an assistant and ficient 32P to carry out investigations about milk formation, "It knew him so well as to become his principal biographer. She is always a sign of appreciation to keep letters, but it is a sign published in 1976 a delightful portrayal of him and his methods of utmost appreciation to treat letters as we did treat yours. A in the laboratory, as well as of some of his warm and kindly trace of phosphorus penetrated the envelope ... and this in­ interpersonal relationships (18 ), ·'George Hevesy and His duced us to dissolve your letter and to recover the trace of Concept of Radioactive Indicators-In Retrospect." "He was phosphorus it contained. When historians will once describe possessed by his scientific ideas which dominated his thinking your life history I hope they won't omit this incident, showing so much he did not have time for other activities." Her histor­ how precious your letters were." In those days radioisotopes ical essay was the first paper to be published in the new simply were airmailed in ordinary envelopes! Hevesy was European Journal of Nuclear Medicine (18 ). highly appreciative of Lawrence's generosity, for the cyclotron A decade earlier, Levi published a shorter sketch about in Berkeley was the only major source of the radionuclides he Hevesy (19 ). His "inexhaustible stream of new ideas, his dy­ needed to pursue the numerous ideas overflowing from his namic personality, his incredible memory for everything done mind. or read, and his apparently effortless endurance-he never I first met Hevesy at the Symposium on Radiobiology held at could sleep more than a few hours each night-brought about Oberlin College in 1950. There he presented an extensive his ever-presence at all odd hours of the day in different paper on "Ionizing and Cellular Metabolism" (13 ). laboratories scattered all over the city of Copenhagen." Hevesy always was ahead of his time! He was among the first Her obituary concerning Hevesy in 1967 (20) sketched his to apply radioactive indicators in studies of the effects of lifework in summary outline. It includes a photograph of him ionizing (1 ). Also, he and his colleagues first used and a reliable source of reference to serve as a complete and indicator tracer methods to study cancerous tumors. correct bibliography of his 397 publications.

VOLUME 24, NUMBER 4, DECEMBER 1996 293 "Hevesy wrote practically everything by hand" (1 8 ). The tion of the magnificent scientific legacy we derive from Hevesy treasured longhand letters I received from him reflect the and recognize him to have been our inspirational leader and warmth, humility, modesty and considerateness of the man. our principal intellectual forefather. His extensive correspondence resulted in his stating a point laconically. "Radioiodine-123 is a most useful substance" ap­ peared in his letter to me in July 1962. REFERENCES One finds much in McCagg's documentary book in 1972 I. Hevesy G. Ad•·mfltres in radioisotope research. New York: Pergamon Press: (21) about the origins of five scientists in modern 1962. whom he considered to be geniuses, and Hevesy was one of 2. Hevesy G. The ahsorption and translocation of lead by plants. A contrihution them. to the application of the method of radioactive indicators in the investigation Hevesy was born August 1, 1885 in , Hungary and of the change of suhstance in plants. Biochern J 1923:17:439-445. completed his secondary school education at the Piarist Gram­ 3. Hcvcsy G. Pancth F. Die liislichkeit des bleisulfids und hlcichromats. Z Anol)l Chern 1913;H2:323-328. mar School. His academic studies began at the University of 4. Paneth F, Hevesy G. Ober radioelemente als indikatoren in der analytischen Budapest, continued in Berlin, and he received his PhD degree Chemic. Monatsh Chern 1913;34:1401-1407. in chemistry and physics from the in 5. Hevesy G, Pancth F. A manual of radioactivity, 2nd ed .. London: Oxford 1908. After appointments in many laboratories in several coun­ University Press; 1938. o. Joliot F, Curie I. Artificial production of a new kind of radio-clement. Nalllre tries, he became professor of at Freiburg, 10 Fehruary 1934;133:201-202. 1926-1935. He left there to go to the Bohr Institute in Copen­ 7. Chievitz 0, Hevesy G. Radioactive indicators in the study of phosphorus hagen, where he stayed during the occupation until 1943 when metabolism in rats. Nalllre 1935;136:754-755. he settled down in the Institute for Organic Chemistry of the K Myers WG. The first radioindicator study in the life sciences with a man­ University of Stockholm. He died in a clinic in Freiburg on July made radionuclide. J Nuc/ Med 1975:16:1106-1108. 5, 1966. lJ. Hcvcsy G. Radioactire indicators. New York: Interscicncc Puhlishers: 194S. 10. Hinc GJ. The inception of photoelectric scintillation detection commemo­ Numerous honors were bestowed on Hevesy in addition to rated after three decades. J Nucl Med 1977;18:867-871. the Nobel Prize in 1943 and the Atoms for Peace Award in II. Hevcsy G. Some applications of isotopic indicators. In les Prir Nohel en 1959. He regarded especially highly his election to be a foreign 1940-194./. Stockholm: Norstedt & Siiner; 1946:95-127. member of the Royal Society of London and his being awarded 12. Hevesy GC. The application of radioactive indicators in hiochcmistry. J the by it in 1949. He received more than a dozen Chem Soc June. 1951:1618-1639. 13. Hevesy G. Ionizing radiation and cellular metabolism. In: .~rmpusium on honorary degrees; and he may have been unique insofar as four radiohiolo!fo'· New York: Wiley: 1952:189-215. of them were honorary doctor of medicine degrees. Four fac­ 14. Myers WG. Applications of the cyclotron and its products in hiomedicinc. ulties of medicine thus indicated the esteem in which they held Unpuhlished MD thesis, 1941. Hevesy for his basic contributions to medicine. 15. Hevesy G. Marie Curie and her contemporaries: the Bccquercl-Curie Me­ Nuclear medicine is endowed with an especially rich and morial Lecture. J Nucl Med 1961:2:169-182. I o. Wagner J r HN. Personal communication, 1977. variegated heritage. Paraphrasing Newton, "We stand on the 17. Yalow RS. Radioimmunoassay: a probe for the fine structure of hiological shoulders of giants;" and our activities stem from an integra­ systems. Science 16 June 1978:200:1236-1245. tion of some of the insights of no less than three dozen Nobel I H. Levi H. George Hcvesy and his concept of radioactive indicators-in retro­ laureates and the sagacity of many other gifted scientists. spect. Eurl Nucl Med 1976: I :3-10. Distinctly notable among our forebears was Georg Charles de 19. Levi H. The development of the tracer method, 1935-1945. lnt J Appl Rad & Isotopes 1965;16:511-513. Hevesy. At the end of the first 25 yr of the Society of Nuclear 20. Levi H. George de Hcvcsy. 1967:A98:1-24. Medicine, we opportunely and appropriately demonstrate our 21. McCagg Jr WO. Jewish nobles and geniuses in modem Hungmy, New York: maturity when we acknowledge our cognizance and apprecia- Columbia University Press; 1972.

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